Akt-FOXO3a signaling axis dysregulation in human oral squamous cell carcinoma and potent efficacy of FOXO3a-targeted gene therapy.

Phosphoinositide-3-kinase (PI3K)/Akt pathway has been shown to be activated in oral squamous cell carcinoma (OSCC). Activation of Akt suppresses FOXO transcription factor-mediated growth arrest and apoptosis in various cancers. We investigated FOXO3a and phosphor(p)-Akt expression and potential efficacy of FOXO3a-targeted gene therapy in OSCC. Low expression of FOXO3a was negatively associated with overexpression of p-Akt and histological grade using immunohistochemistry. Akt-FOXO3a axis was also examined by detection of FOXO3a expression after induction or inhibition of Akt activity in Tca8113 OSCC cells. Transfection of a constitutively active form of FOXO3a (FOXO3a(3A)) in OSCC cells induced significant G₁-phase arrest and apoptosis as compared with control and transfection of a wild-type FOXO3a (FOXO3a(WT)). Stable FOXO3a(3A) transfectant OSCC cells also revealed the most potent growth inhibition effect in vivo. Furthermore, the downstream effects of FOXO3a activation were found to be inhibition of CDK4/6 and cyclin D1, and accumulation of p27 and Bim. We also found that transcription of FOXO1 and FOXO4 were stimulated by FOXO3a. Our results suggest that FOXO3a activity may be important in tumorigenesis and development of OSCC. Akt-FOXO3a axis inhibition-mediated constitutively active FOXO3a induces significant growth inhibition and FOXO3a activation may present a potent target-based therapeutic strategy for OSCC therapy.